Abstract
Dysregulated expression of histone methyltransferases and demethylases is an emerging epigenetic mechanism underlying cancer development and metastasis. We recently showed that the histone H3 lysine 36 (H3K36) demethylase KDM2A (also called FBXL11 and JHDM1A) is necessary for tumorigenic and metastatic capabilities of KDM2A-overexpressing non-small cell lung cancer (NSCLC) cells. Here, we report that KDM2A transcriptionally represses the histone deacetylase 3 (HDAC3) gene by removing methyl groups from dimethylated H3K36 at the HDAC3 promoter in KDM2A-overexpressing NSCLC cells. KDM2A depletion reduced expression levels of cell cycle-associated genes (e.g. CDK6) and cell invasion-related genes (e.g. NANOS1); these levels were rescued by ectopic expression of KDM2A but not its catalytic mutant. These genes were occupied and down-regulated by HDAC3. HDAC3 knockdown significantly recovered the proliferation and invasiveness of KDM2A-depleted NSCLC cells as well as the levels of CDK6 and NANOS1 expression in these cells. Similar to their previously reported functions in other cell types, CDK6 and NANOS1 were required for the proliferation and invasion, respectively, of KDM2A-overexpressing NSCLC cells. In a mouse xenograft model, HDAC3 depletion substantially restored the tumorigenic ability of KDM2A knockdown cells. These findings reveal a novel cancer-epigenetic pathway in which the antagonistic effect of KDM2A on HDAC3 expression releases cell cycle-associated genes and cell invasion-related genes from HDAC3 repression and indicate the importance of this pathway for tumorigenicity and invasiveness of KDM2A-overexpressing NSCLC cells.
Highlights
Overexpression of the epigenetic repressor KDM2A promotes lung tumorigenesis
Consistent with our previous study showing that KDM2A positively regulates the S phase cell population and cellular invasiveness [16], the results presented here indicate that KDM2A enhances expression of the cell cycle-associated genes CDK6 and NEK7 and the cell invasion-related genes NANOS1 and RAPH1 in KDM2A-overexpressing non-small cell lung cancer (NSCLC) cells
Our current study uncovered the molecular mechanism in which KDM2A-mediated repression of histone deacetylase 3 (HDAC3) expression may antagonize the transcriptional repression of cell cycle-associated genes and invasiveness-related genes by HDAC3 in KDM2A-overexpressing lung cancer cells (i.e. KDM2A ٜ HDAC3 ٜ cell cycle/invasiveness genes (e.g. CDK6 and NANOS1)) (Fig. 10G)
Summary
Overexpression of the epigenetic repressor KDM2A promotes lung tumorigenesis. Results: Transcriptional inhibition of HDAC3 expression by KDM2A releases cell cycle and proinvasive genes from HDAC3mediated repression and positively regulates cell proliferation and invasiveness. KDM2A depletion reduced expression levels of cell cycle-associated genes (e.g. CDK6) and cell invasion-related genes (e.g. NANOS1); these levels were rescued by ectopic expression of KDM2A but not its catalytic mutant. These genes were occupied and down-regulated by HDAC3. In a mouse xenograft model, HDAC3 depletion substantially restored the tumorigenic ability of KDM2A knockdown cells These findings reveal a novel cancer-epigenetic pathway in which the antagonistic effect of. KDM2A on HDAC3 expression releases cell cycle-associated genes and cell invasion-related genes from HDAC3 repression and indicate the importance of this pathway for tumorigenicity and invasiveness of KDM2A-overexpressing NSCLC cells. In lung adenocarcinomas, activating mutations for oncogenes frequently occur in K-RAS and epidermal growth factor receptor gene, whereas mutations in tumor suppressor genes, such as LKB1, are
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